Over the first five years of funding of this program project grant (PPG), our laboratory has been[unreadable] applying an interdisciplinary approach for defining metabolic abnormalities of liver, pancreatic islet[unreadable] beta-cells, and skeletal muscle in diabetes and obesity. Over the same time period, other members of[unreadable] this PPG team have developed technologies for functional imaging, targeted delivery of genes and[unreadable] other molecular cargo, and customized gene activation switches. The most compelling advances[unreadable] made by the PPG team have occurred in the area of pancreatic islet biology and related technologies.[unreadable] We have therefore chosen to focus the competitive renewal of this application on development of new[unreadable] strategies for understanding and reversing beta-cell dysfunction of type 2 diabetes. The goal of this[unreadable] project (Project 1) is to investigate and validate novel pathways for control of beta-cell function and growth[unreadable] that have emerged from our work in the prior funding period. The project will make extensive use of[unreadable] extraordinary technologies resident in Core B for beta-cell specific gene delivery in adult animals, and in[unreadable] Core C for comprehensive MS- and NMR-based metabolic analysis of islets and beta-cell lines. The[unreadable] specific aims of the project are: 1) To investigate mechanisms by which manipulation of the[unreadable] homeodomain transcription factor Nkx6.1 and its target genes affect glucose-stimulated insulin[unreadable] secretion (GSIS) in pancreatic islets; 2) To investigate mechanisms by which manipulation of the[unreadable] homeodomain transcription factor Nkx6.1 and its target genes affect pancreatic islet growth; 3) To test[unreadable] the potential protective or restorative effect of Nkx6.1 and its target genes in preservation of beta-cell[unreadable] mass and function in cellular and animal models of type 2 diabetes.